GroupID: 14a

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: These 2/3 patients with a Q164* (c.490C>T) mutation had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164* (c.490C>T)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 223228 https://www.ncbi.nlm.nih.gov/clinvar/variation/223228/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q164* (c.490C>T)

MultipleGeneVariants: N/A

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was found in 2 VHL type 1 family of 8 and of 7 individuals (family ID 2956; 2693), using PCR and SSCP sequencing. The mutation of c.226_228delTTC was referred to in the paper by c.439delTTC due to a difference in transcript sequence. In the first, Family 2956, 2/8 members had a retinal angioma (hemangioma), 4 had RCC, and 5 members had CNS hemangioblastoma. In Family 2693 3/7 members had a retinal angioma (hemangioma), 3 had RCC, and 3 members had CNS hemangioblastoma. This is possibly previously published in PMID 9829911, as well as one member in a future publication: PMID: 32179488

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 4 VHL type 1 family members (family ID 3315), using PCR and SSCP sequencing. The mutation of c.332G>A was referred to in the paper by c.545G>A due to a difference in transcript sequence. 1 of 4 individuals were identified with retinal hemangioblastomas, 2 with CNS hemangioblastomas, and 2 with renal cell carcinoma. This was possibly previously published in PMID 9829911

GroupID: 4480

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 2 family members recorded with this mutation.

GroupPresentingHPOs: HP:0009711; HP:0010797 (retinal capillary hemangioma, hemangioblastoma)

GroupHPOFreeText: both (2) members had CNS hemangioblastoma, and 1 member had retinal angioma (hemangioma)

GroupNotHPOs: HP:0002666; HP:0005584 (pheochromocytoma, renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V166D (c.497T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L237D (c.710T>A)

ClinVarID: 625254 https://www.ncbi.nlm.nih.gov/clinvar/variation/625254/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V166D (c.497T>A)

MultipleGeneVariants: N/A

PatientID: 265

KindredID: 104

Case: M, 48Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 265) has multiple family members who presented with VHL symptoms but were unconfirmed with the mutation, due to no DNA sample being available or due to death before diagnosis. The proband's son (patient 266) presented with a CNS hemangioblastoma at 19 and retinal angioma at 27. Their first brother (brother 1, patient 267) presented with a CNS hemangioblastoma at 36 and a retinal angioma at 46. Their nephew (son of brother 1, patient 267) presented with a retinal angioma at 16. Their second brother (brother 2, patient 268) had a CNS hemangioblastoma at 30, retinal angioma at 20, and renal cell carcinoma at 41. The proband's second nephew (son of brother 2, patient 269) had a retinal angioma at age 16.

CasePresentingHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0002666 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Pheochromocytoma)

CaseHPOFreeText: The proband presented at age 48 with renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma.

CaseNotHPOs: HP:0009711; HP:0010797 (Retinal capillary hemangioma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: Exon 2 Deletion (c.341-?_463+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2 Deletion

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 8

Case: M, 66Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0009711; HP:0010797 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Retinal capillary hemangioma, Hemangioblastoma)

CaseHPOFreeText: The proband, patient 26, presented with CNS hemangioblastoma at age 66, retinal angioma at age 66, renal cell carcinoma at age 37, and pancreatic cysts/ tumors at age 54.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336), and was likely previously published in Wang et al 2014 (24581539).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.Q73* (c.217C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223164; https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Q73* (c.217C>T)

MultipleGeneVariants: N/A

PatientID: A-V5

KindredID: A-V5

Case: F, 37Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0030405 (Pheochromocytoma, Pancreatic endocrine tumor)

CaseHPOFreeText: Bilateral pheochromocytoma and pancreatic islet cell carcinoma. Diagnosed with VHL type 2.

CaseNotHPOs: HP:0010797; HP:0009711; HP:0001737; HP:0005584 (Hemangioblastoma, Pancreatic cysts, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 25078357

SupplementalData: N/A

Variant: p.A149T (c.445G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223213, https://www.ncbi.nlm.nih.gov/clinvar/variation/223213/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: A149T (c.445G>A)

MultipleGeneVariants: N/A

PMID: 16142346

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.P71Lfs*61 (c.211_212insT) germline variant of the VHL gene was detected in a family (ID 96). Members 5997 and 5993 have unknown renal involvement. Member 5999 presented with mild renal disease. The paper states that this family is previously reported in PMID 12202531, where 1 patient with this mutation is reported and assumed to be part of this family.

GroupID: 411

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 members of this family were found to have the c.500G>A germline variant of the VHL gene. Member 9710 presented with mild renal disease (RCC) and members 13888 and 12271 had unknown renal involvement. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID: 313

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 members of this family were found to harbor the c.340+1_340+5delGTACG germline variant of the VHL gene. Members 7171 and 7170 had unknown renal involvement. Member 5545 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 9829912, where 1 individual is reported to have the “IVS1+1del5” splice site variant which is assumed to correspond to a member of the current family.

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: c.340+2_340+6del

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357098, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340%2B1_340%2B5del

gnomAD: N/A

VariantEvidence: Variant is reported as c.340+1_340+5del and was mapped to c.340+2_340+6del. Authors state that this mutation is predicted to disturb the splicing process.

MutationType: splice_site_variant; deletion; minus_2_frameshift_variant

CivicName: Splice Site (c.340+2_340+6del)

MultipleGeneVariants: N/A

PatientID: 13773

KindredID: 599

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.F76_C77del (c.226_231del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573130179, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573130179

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion; deletion

CivicName: F76_C77del (c.226_231del)

MultipleGeneVariants: N/A

PatientID: 5730

KindredID: 269

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously published individuals could alternatively correspond to family 1005.

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.L188P (c.563T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625266, https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 77

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 77

CasePresentingHPOs: Unknown

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.V170D (c.722T>A)

ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

PatientID: unknown (brother)

KindredID: A

Case: M (deceased), Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. This patient and his one brother were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0002666; HP:0005584 (retinal capillary hemangioma; pheochromocytoma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

Patients presenting with cerebellar hemangioblastomas at the Mexican National institute of Neurology and Neurosurgery to were prospectively enrolled alongside family members, resulting in 84 patients in 7 families with VHL mutations, and subjected to peripheral blood draw and PCR-based mutation screening, as well as full clinical screening for symptomatic individuals. 19 individuals across two families (Family B and Family C) presented with a c.298dupA mutation, leading to a frameshift (p.T100Nfs 32). Among these individuals, 2 in Family B and 6 in Family C were asymptomatic at the time of screening (ages 2, 7, 9, 12, 13, 17, 20, and 29). Of the 4 symptomatic individuals in Family B, one presented at 44 with cerebellar hemangioblastoma and bilateral retinal angiomas; one presented at 16 with 4 cerebellar hemangioblastomas, 1 bulbar hemangioblastoma, 1 spinal hemangioblastoma, bilateral retinal angiomas, pancreatic cysts, and kidney cysts; one presented at age 26 with cerebellar hemangioblastoma, bilateral retinal angiomas, pancreatic cysts, kidney cysts, and renal cell carcinoma; and one presented at 28 with 1 cerebellar hemangioblastoma. Of the 7 symptomatic individuals in Family C, one presented at 45 with cerebellar hemangioblastoma, pancreatic cysts, kidney cysts, and renal cell carcinoma; one presented at age 21 with epididymal cystadenoma; one presented at 36 with 2 cerebellar hemangioblastomas, pancreatic cysts, kidney cysts, hepatic cysts, adrenal cysts, and bilateral renal cell carcinomas; one presented at 20 with spinal hemangioblastoma, pancreatic cysts, and kidney cysts; one presented at 13 with 2 spinal hemangioblastomas, one presented at 13 with cerebellar hemangioblastoma, one presented at 30 with cerebellar hemangioblastoma, pancreatic cysts, and kidney cysts. They were previously published in PMID: 20064270, however with a reportedly different variant: p.G34Rfs98 (c.99_100insA).

GroupID: 19

DiseaseAssertion: assumed VHL

GroupSize: 24

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: 47.8Y +/- 12.7Y

GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 10 families with 24 members total were described, and phenotypic information was given for this group.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts, pheochromocytoma)

GroupHPOFreeText: 15 of the 24 members presented with CNS hemangioblastoma (with a mean age of onset of 35.6Y), retinal capillary hemangioma in 4 members (at the mean age of 23.0Y), renal cell carcinoma in 10 members (at the mean age of 38.3Y), pancreatic cysts in 5 members (at the mean age of 37.2Y), and pheochromocytoma in 9 members (at the mean age of 36.3Y)

GroupNotHPOs: HP:0009715 (papillary cystadenoma of the epididymis)

GroupNotHPOFreeText: No members had a papillary cystadenoma of the epididymis genital system tumor (epididymis or broad ligament)

GroupPreviousTesting: N/A

PreviouslyPublished: 24581539 (family #11); 29330336 (as 7 families of 18 people); 28388566 (family #78, 79, 80, 81, 82, 83)

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 160

KindredID: 160

Case: Sex Unknown, 14Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0002666; HP:0000107; HP:0001732 (Retinal capillary hemangioma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

CaseHPOFreeText: Retinal hemangioblastoma, pheochromocytoma, renal cystic lesion and pancreatic cyst or tumor.

CaseNotHPOs: HP:0006770; HP:0010797 (Clear cell renal cell carcinoma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.L178P (c.533T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant noted as c.533C>T/p.L178P which was assumed to be c.533T>C.

MutationType: missense_variant;transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 246

KindredID: 246

Case: Sex Unknown, 26Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0006770 (Hemangioblastoma, Retinal capillary hemangioma, Clear cell renal cell carcinoma)

CaseHPOFreeText: CNS and retinal hemangioblastoma and clear cell renal cell carcinoma.

CaseNotHPOs: HP:0002666; HP:0000107; HP:0001732 (Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Partial Deletion (0.7kb)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Partial deletion of 0.7kb

MultipleGeneVariants: N/A

PatientID: 105

KindredID: 105

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but no details provided.

CasePresentingHPOs: HP:0000107; HP:0009711; HP:0010797; HP:0001732 (Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma, pancreatic cyst or tumor, renal cystic lesion and retinal hemangioblastoma.

CaseNotHPOs: HP:0006770; HP:0002666 (Clear cell renal cell carcinoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.P86A (c.256C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93327, https://www.ncbi.nlm.nih.gov/clinvar/variation/93327/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: P86A (c.256C>G)

MultipleGeneVariants: N/A

PatientID: 249

KindredID: 249

Case: Sex Unknown, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0006770, HP:0000107 (clear cell renal cell carcinoma, renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711,HP:0010797, HP:0001737, HP:0002666 ( retinal capillary hemangioma, hemangioblastoma, pancreatic cyst, pheochromocytoma )

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

Variant: p.P86L(c.257C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: CA020186 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.257C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86L(c.257C>T)

MultipleGeneVariants: N/A

PatientID: VI-6

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL (Asymptomatic)

FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0009711; HP:0002666; HP:0002668 (Renal cell carcinoma, Retinal capillary hemangioma, Pheochromocytoma, Paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

SupplementalData: N/A

Variant: p.Y112H (c.334T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: Sex Unknown, 38Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: Also belonging to family 1, patients 2 and 3 had VHL diagnoses and phenotypes. Their relation is not clear.

CasePresentingHPOs: HP:0002668, HP:0002666; HP:0030405 (Paraganglioma, pheochromocytoma, pancreatic endocrine tumor)

CaseHPOFreeText: The patient developed PPGL at 38Y of age, and a PNET at 38Y.

CaseNotHPOs: HP:0010797; HP:0005584; HP:0009711; HP:0001737; HP:0000107 (hemangioblastoma, renal cell carcinoma, retinal capillary hemangioma, pancreatic cyst, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114S (c.340G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 583094 https://www.ncbi.nlm.nih.gov/clinvar/variation/583094/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G114S (c.340G>A)

MultipleGeneVariants: N/A

PatientID: 31

KindredID: 22

Case: Sex Unknown, 32Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: stated as a familial VHL. 1 other family member (patient 30) with that same mutation was stated with an age of 56. This patient has RCC, renal cysts, pancreatic cysts, and CNS hemangioblastoma and retinal capillary hemangioblastomas.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0005584; HP:0000107 (hemangioblastoma, pancreatic cyst, renal cell carcinoma, renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002668, HP:0002666; HP:0009711; HP:0030405; (Paraganglioma, pheochromocytoma, retinal capillary hemangioma, pancreatic endocrine tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

PatientID: II-3

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Both of the patient’s brothers (Patient II-4 and II-1), the patient’s sister (II-5), and the patient’s son (III-3) were clinically diagnosed with VHL disease. Patient II-1 presented with RCCC at age 33 and CH at age 41. He carried the mutation NM_000551.3:c.269A>T. Patient II-4 presented with RCCC at age 53, and carried the same mutation. Patient III-3 presented with CH and carried the same mutation. The patient’s sister (Patient II‐5) was deceased and had an undetermined mutation. Patient II‐5 died of a ruptured CH. The patient’s parents (Patient I-1 and I-2) were also deceased from other causes. The patient’s grandson (Patient IV‐1) was healthy and did not carry the mutation.

CasePresentingHPOs: HP:0006770 (Renal clear cell carcinoma)

CaseHPOFreeText: The patient died from advanced RCCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: N/A

LegacyVariant: N/A

ClinVarID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: N/A

CivicName:N/A

MultipleGeneVariants: N/A

PatientID: None

KindredID: 6

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL. Parents underwent genetic testing and were not found to harbor the P102Rfs*57 (c.305del) germline variant of the VHL gene, confirming a de novo mutation in the current patient.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0002894 (Hemangioblastoma, Renal cell carcinoma, Neoplasm of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma, pancreatic cystadenoma and Renal carcinoma.

CaseNotHPOs: HP:0009711; HP:0002894; HP:0002666 (Retinal capillary hemangioma, Neoplasm of the pancreas, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P102Rfs*57 (c.305del)

LegacyVariant: N/A

CaseProblemVariantFreeText:

ClinVarID: N/A

CAID: CA658820710, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.305del

gnomAD: N/A

VariantEvidence: This variant was not found in 120 alleles from normal subjects in the Brazilian population.

MutationType: deletion; minus_1_frameshift_variant

CivicName: P102fs (c.305del)

MultipleGeneVariants: N/A

Germline mutations were found in 20 Brazilian VHL probands and their families. The F76del (c.226_228del) germline mutation was found in a VHL type 1 family of 5 affected individuals (VHL family 1). Of the 5 affected family members four patients had hemangioblastomas of the central nervous system and 2 had renal carcinoma. In family 1 genetic testing was performed in a non-symptomatic boy, since no relatives were alive for testing. Although many members of this family had already presented with HB, the diagnosis of VHL was confirmed after necropsy of the proband’s father, who died at 37 years from complications following emergency surgery for cerebellar HB. The necropsy showed many occult lesions related to VHL, including RC, multiple pancreatic and renal cysts, and cystadenoma of the epididymis. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

PMID: 26796762

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: III:11

KindredID: 1

Case: F, 75, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father (II:3) had a brain tumour at age 53 and died at age 78. The patient's paternal aunt (II:1) died of stomach cancer at age 80. The patient's paternal grandfather died at age 50 due to a brain tumour. The patient had seven siblings, five of whom underwent genetic testing. Two were found to carry the mutation but both were asymptomatic (patient III:2 and III:3). The patient's sister (III:2) had three children all of whom carried the P25L mutation and were asymptomatic (IV:4 and IV:6) except patient IV:2 who presented with a retinal hemangioma and renal cyst. Her niece, (IV:2) had three children and one was found to carry the mutation. The patient's brother (III:3) had six children one of whom died due to clear cell renal carcinoma at age 48 but did not carry the P25L mutation (IV:7). The patient had three unaffected children who did not carry the mutation. Of the 13 family members tested, V:2, IV:4, IV:6, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. Refer to Figure 1 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Ongoing clinical follow up of the individuals with P25L over a period of 5 years has continued to show no evidence of additional clinical involvement of VHL disease.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P25L (c.74C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 43

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 5 patients with the given mutation belonging to VHL family 43

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0000107 (retinal capillary hemangioma, hemangioblastoma, renal cyst)

GroupHPOFreeText: 5 patients have retinal angioma, 2 with hemangioblastoma and 2 with renal cyst

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R167Q (c.713G>A)

ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL54

Case: Sex unknown, Age unknown, German

DiseaseAssertion: assumed VHL

FamilyInfo: One patient with the given mutation is stated to belong to VHL family 54

CasePresentingHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioma, pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.Y98H (c.505T>C)

ClinVarID: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: CA020246 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.292T%3EC

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A - Not specified

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: VHL syndromic HB

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q96_P102del (c.287_307del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573106190 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573106190

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: Q96_P102del (c.287_307del)

MultipleGeneVariants: N/A

PMID: 30853203

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

GroupID/ KindredID: 3786NCI

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3786NCI. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

SupplementalData: N/A

Variant: p.L178P (c.533T>C)

LegacyVariant: p.L178P (c.746T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 53CE

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 53CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V74G (c.221T>G)

LegacyVariant: p.V74G (c.434T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70042528 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.221T>G

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V74G (c.221T>G)

MultipleGeneVariants: N/A

Of 246 patients affected with von Hippel-Lindau disease, 64 patients (26%) from 38 families had pheochromocytoma, including 33 newly diagnosed during screening studies and 31 treated before screening at NIH. Germline mutations in the VHL gene were determined from sequencing peripheral blood using PCR, SSCP (single-strand conformation polymorphism), and Southern Blotting. Family 4578 was found with c.233A>G mutation in the VHL gene (legacy notation c.446A>G converted to NM_000551.3). It should be noted that the paper describes the amino acid change to be Asp to Ser but, there is no Asp at position 233. This is assumed to be a mistake, with the correct amino acid change being Asn to Ser. 4/8 had pheochromocytoma, 7/8 had renal cell carcinoma, 5/8 had CNS hemangioblastoma, 3/8 had retinal angiomas and 2/8 had cysts.

PatientID: III:10

KindredID: 1

Case: M, Age Unknown (deceased), Chinese

DiseaseAssertion: VHL

FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

CasePresentingHPOs: N/A

CaseHPOFreeText: unknown phenotype, however they were said to be affected

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: Death before genetic diagnostic, however presumed by authors due to extensive family history (See pedigree).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

KindredID: 21

GroupID: 55

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.21 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is not present in this kindred.

GroupPresentingHPOs: N/A

GroupHPOFreeText: No phenotypic information is listed for this kindred.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: Pheochromocytoma was not observed in any members of the affected patient(s)' family (VHL type 1).

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q195* (c.583C>T)

LegacyVariant: c.796C>T (p.Q266*)

CaseProblemVariantFreeText: N/A

ClinVarID: 428794, https://www.ncbi.nlm.nih.gov/clinvar/variation/428794/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q195* (c.583C>T)

MultipleGeneVariants: N/A

atientID: None

KindredID: 15

Case: Sex Unknown, 71Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: All VHL mutation carriers of 18 years or older who underwent surveillance according to Dutch VHL guidelines between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU) were included. Patients with VHL-disease subtype 2C (pheochromocytoma only) were excluded.

CasePresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0030405; HP:0000107; HP:0001737; HP:0002666 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Renal cyst, Pancreatic cysts, Pheochromocytoma)

CaseHPOFreeText: VHL Type 2a/b.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

Variant: p.V170D (c.509T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625256, https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported a nucleotide deletion (i.e. 476G>C) which coincides with legacy variant nomenclature (AF010238.1) and was mapped to c.263G>C (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 8 had p.Trp88Ser mutation. All 5 examined family members were affected with renal cell carcinoma. Other demographics of the members were not described.

GroupID: 39

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711(retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797, HP:0002666, HP:0005584 (hemangioblastoma, pheochromocytoma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86L(c.257C>T)

LegacyVariant: p.P157L (c.470C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86L(c.257C>T)

MultipleGeneVariants: N/A

Clinical case report of a 32-year-old male presenting with hematuria. Blood and tissue samples were isolated and samples were paired-end multiplex sequenced on the Illumina HiSeq platform to a median target depth of >100×.A germline de novo nonsense mutation, c.358A>T leading to an early stop codon, was confirmed on exon 3 of the VHL gene. The man also presented with multiple renal cysts; renal cell carcinoma; capillary retinal angiomas; brain hemangioma; and spinal hemangioma. Confirmation of paternity and maternity was not described, therefore assumed de novo.

Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. 15 patients were found with this missense variant in the VHL gene. The ages of the patients were represented as a range, 16-71Y (mean 45). The phenotypes were presented together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumor, pheochromocytoma, renal cysts, and pancreatic cysts. Family history was not described. This cohort was published later in PMID 31087189.

PMID: 31673890

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: None

KindredID: 39

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Retinal angioma.

CaseNotHPOs: HP:0005584; HP:0001732; HP:0010797 (Renal cell carcinoma, Abnormality of the pancreas, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.P86L (c.257C>T)

LegacyVariant: c.470C>T

CaseProblemVariantFreeText: N/A

ClinVarID: 182977, https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: None (father)

KindredID: 1

Case: M, 78Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 37Y old daughter had multiple cysts (RCC) in both kidneys and the same (c.349T>A) mutation

CasePresentingHPOs: HP:0000107; HP:0005584; HP:0006770 (renal cysts; renal cell carcinoma, clear cell renal cell carcinoma)

CaseHPOFreeText: VHL patient underwent left nephrectomy and right partial nephrectomy (subtotal nephrectomy). Histopathological examination revealed clear cell type renal cell carcinoma (RCC)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W117R (c.349T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753664 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.349T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117R (c.349T>A)

MultipleGeneVariants: N/A

PatientID: 2b

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: An unspecified relative (proband - 2a) had the same mutation with renal cell carcinoma, hemangioblastoma, retinal capillary hemangioma, pancreatic cysts and pancreatic endocrine tumors.

CasePresentingHPOs: HP:0005584; HP:0010797; HP:0009711; HP:0002668; HP:0030405 (renal cell carcinoma; hemangioblastoma; retinal capillary hemangioma; pancreatic cyst; pancreatic endocrine tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: 17

KindredID: 17

Case: 20Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711 (hemangioblastoma; retinal capillary hemangioma)

CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The heterozygous missense variant NM_000551.3:c.311G>T was identified on two of her daughters; one was 21Y and one was 17Y. The 21Y daughter had hypertension and a paraganglioma, and the 17Y daughter had a retinal hemangioblastoma.

CasePresentingHPOs: N/A

CaseHPOFreeText: The patient refused a complete staging.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G104V(c.311G>T)

LegacyVariant: N/A

ClinVarID: 223183, http://www.ncbi.nlm.nih.gov/clinvar/variation/223183

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G104V(c.311G>T)

MultipleGeneVariants: N/A

PatientID: None (Proband)

KindredID: 1

Case: M, 18Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The family history revealed VHL in his mother, who died at the age of 40, and in his maternal aunt and grandmother, deceased at 30 and 33 years, respectively. His mother was operated on three times for cerebellar hemangioblastomas, the first at 13 years of age. She had also been treated for bilateral retinal hemangioblastomas since the age of 19. In addition, she had surgery for a renal tumor at the age of 32 and also had pancreatic cysts. She died of the diffuse hemangioblastomas in the posterior fossa. Variant is stated to be previously identified in the family but it is not clear which members have been genetically tested.

CasePresentingHPOs: HP:0006880; HP:0002893; HP:0007663; HP:0001510; HP:0000823; HP:0009711 (Cerebellar hemangioblastoma, Pituitary adenoma, Reduced visual acuity, Growth delay, Delayed puberty, Retinal capillary hemangioma)

CaseHPOFreeText: Referred at the age of 15 for decreased visual acuity of the right eye. Growth failure with short stature for age and lack of pubertal development was noted. This was confirmed by ophthal-mologic examination which also showed bitemporal quadranopsia. Two retinal vascular lesions had already been diagnosed and photocoagulated. Cerebral MRI examination visualized a voluminous pituitary adenoma (confirmed pathologically) with suprasellar extension compressing the optic fibres invading both cavernous sinuses. It also confirmed two small cerebellar hemangioblastomas. On follow-up, MRI showed a persistent pituitary adenoma (confirmed by pathology) with numerous mitoses. A cystic part of the main hemangioblastoma was also noted in the right cerebellum image.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: No renal lesion was found on ultrasound examination. Renal ultrasound examination was persistently normal.

CasePreviousTesting: N/A

PreviouslyPublished: 25494863

SupplementalData: Figure 1

Variant: p.G114R (c.340G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

CAID: N/A

gnomAD:

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G114R (c.340G>C)

MultipleGeneVariants: N/A

A cohort of 314 patients with pheochromocytoma and functional paraganglioma had blood samples collected and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened for mutations. 25 patients had germline VHL mutations, 16 of which had a family history and 9 patients had an apparently sporadic presentation, 11 were male and 14 were female, the median age of diagnosis is 23.9 and range of diagnosis was 4-49. Out of the 25 patients 23 had adrenal tumours, 4 had para-adrenal tumours, and 9 had other VHL lesions (renal tumours and hemangioblastomas). 1 patient with postive family history and/or a syndromic presentation and 1 patient with an apparently sporadic presentation were found with pheochromocytoma or functional paraganglioma and a germline missense VHL mutation (c.533T>C). Other phenotypes unique to the patient are unknown. ACMG: PP4

PatientID: 1

KindredID: 86

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: two RCC tumors were detected in this patient

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C77Lfs*55 (c.227_228insC)

CaseProblemVariantFreeText: NM_000551.3:c.227_228insC automapped to NM_000551.3:c.228dupC

LegacyVariant: p.76 FS (c.441insC)

ClinVarID: N/A

CAID: CA658795177 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_228insC

gnomAD: N/A

VariantEvidence: Tested the tumors for somatic mutations but did not detect any

MutationType: plus_1_frameshift_variant

CivicName: C77fs (c.228dup)

MultipleGeneVariants: N/A

PMID: 8550742

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 9

KindredID: 9

Case: M, 51Y0M, Ethnicity unknown

DiseaseAssertion: pancreatic endocrine tumor

FamilyInfo: None

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: See Table 1 for more information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H191Tfs*11 (c.571delC)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA658795182 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.571delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H191Tfs*11 (c.571delC)

MultipleGeneVariants: N/A

PatientID: 33M

KindredID: 33M

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CohortInfo: Patients with apparently sporadic pheochromocytomas.

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a malignant adrenal pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.*214C(c.641_642insC)

LegacyVariant: p.X > Cys+ 128AA (c.854insC)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189243 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.641_642insC

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: *214C (c.641_642insC)

MultipleGeneVariants: N/A

PatientID: 12

KindredID: 12

Case: F, 41Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Daughter has the same mutation and presented with CNS hemangioblastoma.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: https://doi.org/10.3803/jkes.2006.21.3.239

SupplementalData: N/A

Variant: p.Q73* (c.217C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223164, https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

CivicName: Q73* (c.217C>T)

MultipleGeneVariants: N/A

PMID: 8758206

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

GroupID: 24

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Three registrants from either France or Argentina have the same mutation of c.481C>T.

GroupPresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: A

DiseaseAssertion: assumed VHL

GroupSize: 8

GroupNumberMales: 2

GroupNumberFemales: 6

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: The kindred comprised of 21 individuals over 4 generations. The following members have a confirmed mutation: I:1 (F, deceased), II:2 (F, deceased), III:2 (F, deceased), III:4 (M), III:6 (F), IV:4 (F), IV:6 (M), IV:7 (F, is predicted to be affected). The 3 deceased members had died from VHL related tumors. Another 3 were suffering from VHL, another developed RCC an cHB, and 1 was a VHL carrier. All 8 members had this mutation

GroupPresentingHPOs: HP:0005584; HP:0006880; HP:0009711; HP:0030421 (renal cell carcinoma; cerebellar hemangioblastoma; retinal capillary hemangioma; epidymidal tumor)

GroupHPOFreeText: 5 members had RCC, 5 had multiple cerebellar hemangioblastomas, 2 had retinal capillary hemangioma and 1 had an epidymidal tumor.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: None of the eight VHL carriers of the first kindred had developed pheochromocytoma, and this kindred clearly presents VHL disease type 1

GroupPreviousTesting: N/A

PreviouslyPublished: 7700111

SupplementalData: N/A

Variant: p.S183Cfs*19 (c.548delC)

LegacyVariant: p.183 (c.761delC)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658795184 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.548delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S183fs (c.548delC)

MultipleGeneVariants: N/A

PatientID: 19

KindredID: 1

Case: F, 17Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient was a member of family 1, where 14/32 total patients were diagnosed with VHL. One of which (I-32) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0006748; HP:0030405 (adrenal pheochromocytoma; pancreatic endocrine tumor)

CaseHPOFreeText: Patient presented with his initial VHL-related clinical manifestations at 17Y0M. She had adrenal pheochromocytoma and pancreatic endocrine tumor. She was diagnosed with VHL subtype 2A at age 18Y0M (see table 1).

CaseNotHPOs: HP:0002668 (paraganglioma)

CaseNotHPOFreeText: Patient does not have paraganglioma.

CasePreviousTesting: N/A

PreviouslyPublished: 8550742

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: IX-I

KindredID: 9

Case: M, 68Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history reported.

CasePresentingHPOs: HP:0006748; HP:0002668; HP:0030405; HP:0001737; HP:0006880 (adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, cerebellar hemangioblastoma)

CaseHPOFreeText: Patient presented with adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, and cerebellar hemangioblastoma at age 55Y0M and was diagnosed with VHL type 2A (see table 2).

CaseNotHPOs: HP:0000107; HP:0005584 (renal cyst; renal cell carcinoma)

CaseNotHPOFreeText: Patient negative for renal cell carcinoma and renal cysts.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: NULL (deletion)

MultipleGeneVariants: N/A

Patients with either sporadic or familial pheochromocytoma or paraganglioma diagnosed at or referred to the Cliniques Universitaires Saint Luc (Universite´ catholique de Louvain) from May 2003 to May 2006 had DNA from peripheral blood screened for the coding parts of SDH, VHL and RET genes, performed by SSCP. A VHL germline mutation (D126N) was found in a Belgian patient with sporadic right jugulotympanic paraganglioma, diagnosed at 53, without any other VHL phenotypes. This patient was previously published in 12393546.

PatientID: None

KindredID: VHL10

Case: F, 65Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient had one malignant pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: Table 1 of Supplementary

Variant: p.Y156H (c.466T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756040, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.466T%3EC

gnomAD: N/A

VariantEvidence: The patient had LOH found in the BAC array CGH data.

MutationType: missense_variant;transition

CivicName: Y156H (c.466T>C)

MultipleGeneVariants: N/A

GroupID: 42

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 3 of the 573 patients discussed in this paper were found to have identical variants. This mutation was found in 1 VHL family with 3 patients.

GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0002666 (retinal capillary hemangioma, cerebellar hemangioblastoma, pheochromocytoma)

GroupHPOFreeText: 2 had retinal hemangioblastoma at a mean age of 16Y, one had cerebellar hemangioblastoma at 16Y, and 1 had pheochromcytoma at 14Y.

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/

CAID: N/A

gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C

VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious).

MutationType: splice_site_variant

CivicName: Splice Region (c.340+5G>C)

MultipleGeneVariants: N/A

PatientID: I:1

KindredID: 4

Case: F, 63Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient’s one son (II:3) was found with the same mutation and hemangioblastoma at 22Y and retinal capillary hemangioma at 32Y. Her other son (II:1) died before diagnosis; thus no DNA sample available. He presented with hemangioblastoma at 19Y

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: patient had RCC at 63Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N90I (c.269A>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223172 https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N90I (c.269A>T)

MultipleGeneVariants: N/A

PatientID: N/A (mother)

KindredID: 1

Case: F, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Prior to her daughter being tested, there was no family history of PCC/paraganglioma (PGL), multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1) or VHL. Genetic testing and observation found the mutation (c.361G>C) in her daughter, who also presented with extraadrenal and adrenal pheochromocytoma.

CasePresentingHPOs: HP:0009713; HP:0006748; HP:0030405 (spinal hemangioblastoma, adrenal pheochromocytoma, pancreatic endocrine tumor)

CaseHPOFreeText: MRI of the brain, spine and abdomen revealed multiple, asymptomatic VHL-associated lesions. These included a spinal haemangioblastoma, bilateral T2-hyperintense adrenal lesions (18 mm and 12 mm), subsequently confirmed to be PCCs, and two pancreatic lesions (11 mm and 16 mm), subsequently confirmed to be grade 1 neuroendocrine tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: SDHA, SDHB

SupplementalData: N/A

Variant: p.D121H (c.361G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753752 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.361G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: D121H (c.361G>C)

MultipleGeneVariants: N/A

PatientID: V-23

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A